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1. Disease-modifying therapies for Parkinson disease: lessons from multiple sclerosis

Author

Kalia, Lorraine V., Asis, Angelica, Arbour, Nathalie, Bar-Or, Amit, Bove, Riley, Di Luca, Daniel G., Fon, Edward A., Fox, Susan, Gan-Or, Ziv, Gommerman, Jennifer L., Kang, Un Jung, Klawiter, Eric C., Koch, Marcus, Kolind, Shannon, Lang, Anthony E., Lee, Karen K., Lincoln, Matthew R., MacDonald, Penny A., McKeown, Martin J., Mestre, Tiago A., Miron, Veronique E., Ontaneda, Daniel, Rousseaux, Maxime W. C., Schlossmacher, Michael G., Schneider, Raphael, Stoessl, A. Jon, and Oh, Jiwon

Published
2024
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3. List of contributors

Author

Adams, John S., primary, Amrein, Karin, additional, Anderson, Paul H., additional, Arnold, Leggy A., additional, Arora, Juhi, additional, Artusa, Patricio, additional, Ascherio, Alberto, additional, Asmussen, Niels C., additional, Astier, Anne L., additional, Bak, Min Ji, additional, Bauerle, Kevin T., additional, Belorusova, Anna Y., additional, Benkusky, Nancy A., additional, Bernal-Mizrachi, Carlos, additional, Bhattoa, Harjit P., additional, Bikle, Daniel D., additional, Bilezikian, John P., additional, Binkley, Neil C., additional, Bischoff-Ferrari, Heike A., additional, Bishop, Charles W., additional, Blomberg Jensen, Martin, additional, Boisen, Ida Marie, additional, Boucher, Barbara J., additional, Bouillon, Roger, additional, Boyan, Barbara D., additional, Bradford, Dana, additional, Brancatella, Alessandro, additional, Buburuzan, Laura, additional, Burne, Thomas H.J., additional, Buschittari, Damien, additional, Calkins, Hannah, additional, Calvo, Mona S., additional, Camargo, Carlos A., additional, Campbell, Moray J., additional, Cantorna, Margherita T., additional, Cappellani, Daniele, additional, Carlberg, Carsten, additional, Carmeliet, Geert, additional, Cashman, Kevin D., additional, Ceglia, Lisa, additional, Cetani, Filomena, additional, Chang, Wenhan, additional, Cheadle, Charlotte, additional, Chou, Sharon H., additional, Christakos, Sylvia, additional, Christopher, Kenneth B., additional, Chu, Emily Y., additional, Chun, Rene F., additional, Cleal, Jane K., additional, Cobice, Diego F., additional, Cooper, Cyrus, additional, Coort, Susan L.M., additional, Cui, Xiaoying, additional, Curtis, Elizabeth M., additional, Danilenko, Michael, additional, Darling, Andrea L., additional, David Roodman, G., additional, Dawson-Hughes, Bess, additional, de Jongh, Renate, additional, Demay, Marie B., additional, Dennison, Elaine M., additional, Dixon, Katie M., additional, Dong, Bingning, additional, Doroudi, Maryam, additional, Dusso, Adriana, additional, Dvorzhinskiy, Aleksey, additional, Ebeling, Peter R., additional, Erben, Reinhold G., additional, Evelo, Chris T.A., additional, Eyles, Darryl, additional, Feldman, David, additional, Ferrer-Mayorga, Gemma, additional, Fleet, James C., additional, Forcellati, Marianela, additional, Foster, Brian L., additional, Gafni, Rachel I., additional, Gayan-Ramirez, Ghislaine, additional, Giovannucci, Edward, additional, Girgis, Christian M., additional, Glencross, Drew A., additional, Glorieux, Francis H., additional, Gocek, Elzbieta, additional, Goldfarb, David S., additional, Goltzman, David, additional, González-Sancho, José Manuel, additional, Grant, William B., additional, Groves, Natalie J., additional, Gysemans, Conny, additional, Harrison, Stephanie, additional, Harvey, Nicholas C., additional, Haseltine, Katherine, additional, Hawrylowicz, Catherine M., additional, Hayes, Colleen E., additional, Heckel, John E., additional, Hershberger, Pamela A., additional, Hewison, Martin, additional, Högler, Wolfgang, additional, Holick, Michael F., additional, Hollis, Bruce W., additional, Holt, Rune, additional, Hujoel, Philippe P., additional, Hyppönen, Elina, additional, Ismailova, Aiten, additional, Jablonski, Nina G., additional, Jakobsen, Jette, additional, Janssens, Wim, additional, Jeffery, Louisa, additional, Jenkinson, Carl, additional, Jensen, Marie Bagge, additional, Jetten, Anton M., additional, Jiang, Heng, additional, Johnson, Candace S., additional, Jones, Glenville, additional, Jones, Kerry S., additional, Jüppner, Harald, additional, Kalia, Vandana, additional, Kallay, Enikö, additional, Karapalis, Andrew C., additional, Kaufmann, Martin, additional, Kiely, Mairead, additional, Kim, Hanseul, additional, Kim, Tiffany Y., additional, Kojima, Hiroyuki, additional, Kooij, Ireen, additional, Kovacs, Christopher S., additional, Kremer, Richard, additional, Krieger, Kirsten, additional, Kritmetapak, Kittrawee, additional, Krueger, Diane C., additional, Kumar, Rajiv, additional, Kurihara, Noriyoshi, additional, Lane, Joseph M., additional, Lanham-New, Susan A., additional, Latic, Nejla, additional, LeBoff, Meryl S., additional, Lee, Maija B., additional, Lee, Seong Min, additional, Levine, Michael A., additional, Lewis, Richard, additional, Lewis, Rohan M., additional, Li, Wei, additional, Li, Yan Chun, additional, Lincoln, Matthew R., additional, Lips, Paul, additional, Lisse, Thomas S., additional, Liu, Eva S., additional, López de Maturana, Evangelina, additional, Lugg, Sebastian T., additional, Machado, Christopher J., additional, Maes, Karen, additional, Maestro, Miguel A., additional, Malats, Núria, additional, Malloy, Peter J., additional, Manousaki, Despoina, additional, Marcinkowska, Ewa, additional, Marcocci, Claudio, additional, Martens, Pieter-Jan, additional, Martineau, Adrian R., additional, Mason, Rebecca S., additional, Mathieu, Chantal, additional, Mayne, Phoebe, additional, McGrath, John J., additional, Mehta, Mansi, additional, Mellanby, Richard John, additional, Merchant, Nadia, additional, Meyer, Mark B., additional, Miao, Dengshun, additional, Moon, Rebecca J., additional, Mortensen, Li Juel, additional, Motlaghzadeh, Yasaman, additional, Munger, Kassandra L., additional, Muñoz, Alberto, additional, Nakamichi, Yuko, additional, Narvaez, Carmen J., additional, Nikiphorou, Elena, additional, Nonn, Larisa, additional, Pal, Lubna, additional, Parekh, Dhruv, additional, Pettifor, John M., additional, Pike, J. Wesley, additional, Pilz, Stefan, additional, Pittas, Anastassios G., additional, Pludowski, Pawel, additional, Prosser, David E., additional, Pullagura, Sri Ramulu N., additional, Raphael, Joseph, additional, Rauz, Saaeha, additional, Raza, Karim, additional, Real, Francisco X., additional, Reichrath, Jörg, additional, Richards, J. Brent, additional, Rivadeneira, Fernando, additional, Rochel, Natacha, additional, Roizen, Jeffrey D., additional, Ryan, Brittany A., additional, Sarkar, Surojit, additional, Sarmadi, Fatemeh, additional, Schafer, Anne L., additional, Schepelmann, Martin, additional, Schoenmakers, Inez, additional, Schuit, Frans, additional, Schwartz, Zvi, additional, Scott, Kayla M., additional, Sellmeyer, Deborah E., additional, Sempos, Christopher T., additional, Sepiashvili, Lusia, additional, Seshadri, Mukund, additional, Shane, Elizabeth, additional, Shaurova, Tatiana, additional, Shieh, Albert, additional, Shui, Irene, additional, Singh, Ravinder J., additional, Slominski, Andrzej T., additional, Smith, Karl W., additional, St-Arnaud, René, additional, Stein, Emily M., additional, Studzinski, George P., additional, Suda, Tatsuo, additional, Takahashi, Naoyuki, additional, Taylor, Hugh S., additional, Tebben, Peter J., additional, Thacher, Tom D., additional, Thandrayen, Kebashni, additional, Thickett, David R., additional, Tiosano, Dov, additional, Trajanoska, Katerina, additional, Tu, Chia-Ling, additional, Tuckey, Robert C., additional, Tutaworn, Teerapat, additional, Udagawa, Nobuyuki, additional, Uday, Suma, additional, Unnanuntana, Aasis, additional, van Driel, Marjolein, additional, van Leeuwen, Johannes P.T.M., additional, van Schoor, Natasja, additional, Verlinden, Lieve, additional, Vieth, Reinhold, additional, Vimaleswaran, Karina S., additional, Wagner, Carol L., additional, Wallace, Graham R., additional, Weaver, Connie M., additional, Webb, Daniel A., additional, Welsh, JoEllen, additional, White, John H., additional, Whiting, Susan J., additional, Williams, Emma L., additional, Yahyavi, Sam Kafai, additional, Yamamoto, Keiko, additional, Yates, Clayton, additional, Zagorac, Sladjana, additional, Zhang, Rong Mei, additional, Zhao, Hengguang, additional, Zhou, Ang, additional, and Zittermann, Armin, additional

Published
2024
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5. Author Correction: A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Author

Madireddy, Lohith, Patsopoulos, Nikolaos A, Cotsapas, Chris, Bos, Steffan D, Beecham, Ashley, McCauley, Jacob, Kim, Kicheol, Jia, Xiaoming, Santaniello, Adam, Caillier, Stacy J, Andlauer, Till FM, Barcellos, Lisa F, Berge, Tone, Bernardinelli, Luisa, Martinelli-Boneschi, Filippo, Booth, David R, Briggs, Farren, Celius, Elisabeth G, Comabella, Manuel, Comi, Giancarlo, Cree, Bruce AC, D'Alfonso, Sandra, Dedham, Katrina, Duquette, Pierre, Dardiotis, Efthimios, Esposito, Federica, Fontaine, Bertrand, Gasperi, Christiane, Goris, An, Dubois, Benedicte, Gourraud, Pierre-Antoine, Hadjigeorgiou, Georgios, Haines, Jonathan, Hawkins, Clive, Hemmer, Bernhard, Hintzen, Rogier, Horakova, Dana, Isobe, Noriko, Kalra, Seema, Kira, Jun-ichi, Khalil, Michael, Kockum, Ingrid, Lill, Christina M, Lincoln, Matthew R, Luessi, Felix, Martin, Roland, Oturai, Annette, Palotie, Aarno, Pericak-Vance, Margaret A, Henry, Roland, Saarela, Janna, Ivinson, Adrian, Olsson, Tomas, Taylor, Bruce V, Stewart, Graeme J, Harbo, Hanne F, Compston, Alastair, Hauser, Stephen L, Hafler, David A, Zipp, Frauke, De Jager, Philip, Sawcer, Stephen, Oksenberg, Jorge R, and Baranzini, Sergio E

Subjects
International Multiple Sclerosis Genetics Consortium
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

6. A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Author

Madireddy, Lohith, Patsopoulos, Niklaos A, Cotsapas, Chris, Bos, Steffan D, Beecham, Ashley, McCauley, Jacob, Kim, Kicheol, Jia, Xiaoming, Santaniello, Adam, Caillier, Stacy J, Andlauer, Till FM, Barcellos, Lisa F, Berge, Tone, Bernardinelli, Luisa, Martinelli-Boneschi, Filippo, Booth, David R, Briggs, Farren, Celius, Elisabeth G, Comabella, Manuel, Comi, Giancarlo, Cree, Bruce AC, D'Alfonso, Sandra, Dedham, Katrina, Duquette, Pierre, Efthimios, Dardiotis, Esposito, Federica, Fontaine, Bertrand, Gasperi, Christiane, Goris, An, Dubois, Benedicte, Gourraud, Pierre-Antoine, Hadjigeorgiou, Georgios, Haines, Jonathan, Hawkins, Clive, Hemmer, Bernhard, Hintzen, Rogier, Horakova, Dana, Isobe, Noriko, Kalra, Seema, Kira, Jun-ichi, Khalil, Michael, Kockum, Ingrid, Lill, Christina M, Lincoln, Matthew R, Luessi, Felix, Martin, Roland, Oturai, Annette, Palotie, Aarno, Pericak-Vance, Margaret A, Henry, Roland, Saarela, Janna, Ivinson, Adrian, Olsson, Tomas, Taylor, Bruce V, Stewart, Graeme J, Harbo, Hanne F, Compston, Alastair, Hauser, Stephen L, Hafler, David A, Zipp, Frauke, De Jager, Philip, Sawcer, Stephen, Oksenberg, Jorge R, and Baranzini, Sergio E

Subjects
Human Genome, Autoimmune Disease, Multiple Sclerosis, Genetics, Biotechnology, Brain Disorders, Neurodegenerative, Clinical Research, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Gene Expression Regulation, Genes, Regulator, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Systems Biology, International Multiple Sclerosis Genetics Consortium
Abstract

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.

Published
2019

8. Toward Precision Phenotyping of Multiple Sclerosis

Author

Pitt, David, Lo, Chih Hung, Gauthier, Susan A., Hickman, Richard A., Longbrake, Erin, Airas, Laura M., Mao-Draayer, Yang, Riley, Claire, De Jager, Philip Lawrence, Wesley, Sarah, Boster, Aaron, Topalli, Ilir, Bagnato, Francesca, Mansoor, Mohammad, Stuve, Olaf, Kister, Ilya, Pelletier, Daniel, Stathopoulos, Panos, Dutta, Ranjan, and Lincoln, Matthew R.

Published
2022
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9. An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction.

Author

Sumida, Tomokazu S., Lincoln, Matthew R., He, Liang, Park, Yongjin, Ota, Mineto, Oguchi, Akiko, Son, Raku, Yi, Alice, Stillwell, Helen A., Leissa, Greta A., Fujio, Keishi, Murakawa, Yasuhiro, Kulminski, Alexander M., Epstein, Charles B., Bernstein, Bradley E., Kellis, Manolis, and Hafler, David A.

Subjects
INTERFERON regulatory factors, REGULATORY T cells, ZINC-finger proteins, AP-1 transcription factor, CENTRAL nervous system diseases, TRANSCRIPTION factors
Abstract

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4+FOXP3+ regulatory T cells (Tregs) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of Tregs in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1, which led to destabilization of forkhead box P3 (FOXP3) and Treg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in Tregs from individuals with MS revealed enriched activating protein–1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and Treg dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional Tregs in autoimmune diseases. Editor's summary: Regulatory T cells (Tregs) are known to be dysfunctional in autoimmune diseases, but the cause of this dysfunction has not been fully elucidated. Here, Sumida et al. found that Tregs isolated from individuals with multiple sclerosis, an autoimmune disease of the central nervous system, had increased expression of the short isoform of PR domain zinc finger protein 1 (PRDM1-S), which destabilized expression of the essential Treg transcription factor FOXP3 and induced Treg dysfunction mediated through SGK1, a salt-sensing kinase. Upstream epigenetic analysis revealed a regulatory role for AP-1 and IRF transcription factors in this circuit. The authors detected similar up-regulation of PRDM1-S in other autoimmune diseases, suggesting that PRDM1-S overexpression may be a common feature of Treg dysfunction. —Courtney Malo [ABSTRACT FROM AUTHOR]

Published
2024
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17. A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells

Author

Axisa, Pierre-Paul, primary, Yoshida, Tomomi M., additional, Lucca, Liliana E., additional, Kasler, Herbert G., additional, Lincoln, Matthew R., additional, Pham, Giang H., additional, Del Priore, Dante, additional, Carpier, Jean-Marie, additional, Lucas, Carrie L., additional, Verdin, Eric, additional, Sumida, Tomokazu S., additional, and Hafler, David A., additional

Published
2022
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18. An Autoimmune Transcriptional Circuit Driving Foxp3+Regulatory T cell Dysfunction

Author

Sumida, Tomokazu S., primary, Lincoln, Matthew R., additional, He, Liang, additional, Park, Yongjin, additional, Ota, Mineto, additional, Stillwell, Helen A., additional, Leissa, Greta A., additional, Fujio, Keishi, additional, Kulminski, Alexander M., additional, Epstein, Charles B., additional, Bernstein, Bradley E., additional, Kellis, Manolis, additional, and Hafler, David A., additional

Published
2022
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23. Joint analysis reveals shared autoimmune disease associations and identifies common mechanisms

Author

Lincoln, Matthew R, primary, Connally, Noah, additional, Axisa, Pierre-Paul, additional, Gasperi, Christiane, additional, Mitrovic, Mitja, additional, van Heel, David, additional, Wijmenga, Cisca, additional, Withoff, Sebo, additional, Jonkers, Iris H, additional, Padyukov, Leonid, additional, Consortium, International MS Genetics, additional, Rich, Stephen S, additional, Graham, Robert R, additional, Gaffney, Patrick M, additional, Langefeld, Carl D, additional, Hafler, David A, additional, Chun, Sung G, additional, Sunyaev, Shamil R, additional, and Cotsapas, Chris, additional

Published
2021
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25. List of contributors

Author

Adams, John S., Amrein, Karin, Anderson, Paul H., Arnold, Leggy A., Arora, Juhi, Artusa, Patricio, Ascherio, Alberto, Asmussen, Niels C., Astier, Anne L., Bak, Min Ji, Bauerle, Kevin T., Belorusova, Anna Y., Benkusky, Nancy A., Bernal-Mizrachi, Carlos, Bhattoa, Harjit P., Bikle, Daniel D., Bilezikian, John P., Binkley, Neil C., Bischoff-Ferrari, Heike A., Bishop, Charles W., Blomberg Jensen, Martin, Boisen, Ida Marie, Boucher, Barbara J., Bouillon, Roger, Boyan, Barbara D., Bradford, Dana, Brancatella, Alessandro, Buburuzan, Laura, Burne, Thomas H.J., Buschittari, Damien, Calkins, Hannah, Calvo, Mona S., Camargo, Carlos A., Jr., Campbell, Moray J., Cantorna, Margherita T., Cappellani, Daniele, Carlberg, Carsten, Carmeliet, Geert, Cashman, Kevin D., Ceglia, Lisa, Cetani, Filomena, Chang, Wenhan, Cheadle, Charlotte, Chou, Sharon H., Christakos, Sylvia, Christopher, Kenneth B., Chu, Emily Y., Chun, Rene F., Cleal, Jane K., Cobice, Diego F., Cooper, Cyrus, Coort, Susan L.M., Cui, Xiaoying, Curtis, Elizabeth M., Danilenko, Michael, Darling, Andrea L., David Roodman, G., Dawson-Hughes, Bess, de Jongh, Renate, Demay, Marie B., Dennison, Elaine M., Dixon, Katie M., Dong, Bingning, Doroudi, Maryam, Dusso, Adriana, Dvorzhinskiy, Aleksey, Ebeling, Peter R., Erben, Reinhold G., Evelo, Chris T.A., Eyles, Darryl, Feldman, David, Ferrer-Mayorga, Gemma, Fleet, James C., Forcellati, Marianela, Foster, Brian L., Gafni, Rachel I., Gayan-Ramirez, Ghislaine, Giovannucci, Edward, Girgis, Christian M., Glencross, Drew A., Glorieux, Francis H., Gocek, Elzbieta, Goldfarb, David S., Goltzman, David, González-Sancho, José Manuel, Grant, William B., Groves, Natalie J., Gysemans, Conny, Harrison, Stephanie, Harvey, Nicholas C., Haseltine, Katherine, Hawrylowicz, Catherine M., Hayes, Colleen E., Heckel, John E., Hershberger, Pamela A., Hewison, Martin, Högler, Wolfgang, Holick, Michael F., Hollis, Bruce W., Holt, Rune, Hujoel, Philippe P., Hyppönen, Elina, Ismailova, Aiten, Jablonski, Nina G., Jakobsen, Jette, Janssens, Wim, Jeffery, Louisa, Jenkinson, Carl, Jensen, Marie Bagge, Jetten, Anton M., Jiang, Heng, Johnson, Candace S., Jones, Glenville, Jones, Kerry S., Jüppner, Harald, Kalia, Vandana, Kallay, Enikö, Karapalis, Andrew C., Kaufmann, Martin, Kiely, Mairead, Kim, Hanseul, Kim, Tiffany Y., Kojima, Hiroyuki, Kooij, Ireen, Kovacs, Christopher S., Kremer, Richard, Krieger, Kirsten, Kritmetapak, Kittrawee, Krueger, Diane C., Kumar, Rajiv, Kurihara, Noriyoshi, Lane, Joseph M., Lanham-New, Susan A., Latic, Nejla, LeBoff, Meryl S., Lee, Maija B., Lee, Seong Min, Levine, Michael A., Lewis, Richard, Lewis, Rohan M., Li, Wei, Li, Yan Chun, Lincoln, Matthew R., Lips, Paul, Lisse, Thomas S., Liu, Eva S., López de Maturana, Evangelina, Lugg, Sebastian T., Machado, Christopher J., Maes, Karen, Maestro, Miguel A., Malats, Núria, Malloy, Peter J., Manousaki, Despoina, Marcinkowska, Ewa, Marcocci, Claudio, Martens, Pieter-Jan, Martineau, Adrian R., Mason, Rebecca S., Mathieu, Chantal, Mayne, Phoebe, McGrath, John J., Mehta, Mansi, Mellanby, Richard John, Merchant, Nadia, Meyer, Mark B., Miao, Dengshun, Moon, Rebecca J., Mortensen, Li Juel, Motlaghzadeh, Yasaman, Munger, Kassandra L., Muñoz, Alberto, Nakamichi, Yuko, Narvaez, Carmen J., Nikiphorou, Elena, Nonn, Larisa, Pal, Lubna, Parekh, Dhruv, Pettifor, John M., Pike, J. Wesley, Pilz, Stefan, Pittas, Anastassios G., Pludowski, Pawel, Prosser, David E., Pullagura, Sri Ramulu N., Raphael, Joseph, Rauz, Saaeha, Raza, Karim, Real, Francisco X., Reichrath, Jörg, Richards, J. Brent, Rivadeneira, Fernando, Rochel, Natacha, Roizen, Jeffrey D., Ryan, Brittany A., Sarkar, Surojit, Sarmadi, Fatemeh, Schafer, Anne L., Schepelmann, Martin, Schoenmakers, Inez, Schuit, Frans, Schwartz, Zvi, Scott, Kayla M., Sellmeyer, Deborah E., Sempos, Christopher T., Sepiashvili, Lusia, Seshadri, Mukund, Shane, Elizabeth, Shaurova, Tatiana, Shieh, Albert, Shui, Irene, Singh, Ravinder J., Slominski, Andrzej T., Smith, Karl W., St-Arnaud, René, Stein, Emily M., Studzinski, George P., Suda, Tatsuo, Takahashi, Naoyuki, Taylor, Hugh S., Tebben, Peter J., Thacher, Tom D., Thandrayen, Kebashni, Thickett, David R., Tiosano, Dov, Trajanoska, Katerina, Tu, Chia-Ling, Tuckey, Robert C., Tutaworn, Teerapat, Udagawa, Nobuyuki, Uday, Suma, Unnanuntana, Aasis, van Driel, Marjolein, van Leeuwen, Johannes P.T.M., van Schoor, Natasja, Verlinden, Lieve, Vieth, Reinhold, Vimaleswaran, Karina S., Wagner, Carol L., Wallace, Graham R., Weaver, Connie M., Webb, Daniel A., Welsh, JoEllen, White, John H., Whiting, Susan J., Williams, Emma L., Yahyavi, Sam Kafai, Yamamoto, Keiko, Yates, Clayton, Zagorac, Sladjana, Zhang, Rong Mei, Zhao, Hengguang, Zhou, Ang, and Zittermann, Armin

Published
2023
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26. An autoimmune transcriptional circuit drives FOXP3+regulatory T cell dysfunction

Author

Sumida, Tomokazu S., Lincoln, Matthew R., He, Liang, Park, Yongjin, Ota, Mineto, Oguchi, Akiko, Son, Raku, Yi, Alice, Stillwell, Helen A., Leissa, Greta A., Fujio, Keishi, Murakawa, Yasuhiro, Kulminski, Alexander M., Epstein, Charles B., Bernstein, Bradley E., Kellis, Manolis, and Hafler, David A.

Abstract

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4+FOXP3+regulatory T cells (Tregs) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of Tregsin the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1, which led to destabilization of forkhead box P3 (FOXP3) and Tregdysfunction. This aberrant PRDM1-S/SGK1axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in Tregsfrom individuals with MS revealed enriched activating protein–1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-Sexpression and Tregdysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-Sand epigenetic priming of AP-1/IRF may be key drivers of dysfunctional Tregsin autoimmune diseases.

Published
2024
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30. Activated ß-catenin in Foxp3+regulatory T cells links inflammatory environments to autoimmunity

Author

Sumida, Tomokazu, Lincoln, Matthew R., Ukeje, Chinonso M., Rodriguez, Donald M., Akazawa, Hiroshi, Noda, Tetsuo, Naito, Atsuhiko T., Komuro, Issei, Dominguez-Villar, Margarita, and Hafler, David A.

Abstract

Foxp3+regulatory T cells (Tregcells) are the central component of peripheral immune tolerance. Whereas a dysregulated Tregcytokine signature has been observed in autoimmune diseases, the regulatory mechanisms underlying pro- and anti-inflammatory cytokine production are elusive. Here, we identify an imbalance between the cytokines IFN-? and IL-10 as a shared Tregsignature present in patients with multiple sclerosis and under high-salt conditions. RNA-sequencing analysis on human Tregsubpopulations revealed ß-catenin as a key regulator of IFN-? and IL-10 expression. The activated ß-catenin signature was enriched in human IFN-?+Tregcells, as confirmed in vivo with Treg-specific ß-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional Tregphenotype. Moreover, we identified prostaglandin E receptor 2 (PTGER2) as a regulator of IFN-? and IL-10 production under a high-salt environment, with skewed activation of the ß-catenin–SGK1–Foxo axis. Our findings reveal a novel PTGER2–ß-catenin loop in Tregcells linking environmental high-salt conditions to autoimmunity.

Published
2018
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31. An autoimmune transcriptional circuit drives FOXP3 + regulatory T cell dysfunction.

Author

Sumida TS, Lincoln MR, He L, Park Y, Ota M, Oguchi A, Son R, Yi A, Stillwell HA, Leissa GA, Fujio K, Murakawa Y, Kulminski AM, Epstein CB, Bernstein BE, Kellis M, and Hafler DA

Subjects
Humans, Transcription Factor AP-1 metabolism, Transcription, Genetic, Animals, Chromatin metabolism, Autoimmune Diseases genetics, Autoimmune Diseases immunology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Forkhead Transcription Factors metabolism, Forkhead Transcription Factors genetics, Autoimmunity, Positive Regulatory Domain I-Binding Factor 1 metabolism, Positive Regulatory Domain I-Binding Factor 1 genetics, Multiple Sclerosis genetics, Multiple Sclerosis immunology
Abstract

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4 + FOXP3 + regulatory T cells (T regs ) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of T regs in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1 , which led to destabilization of forkhead box P3 (FOXP3) and T reg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in T regs from individuals with MS revealed enriched activating protein-1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and T reg dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional T regs in autoimmune diseases.

Published
2024
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